ABSTRACT Traumatic brain injury (TBI) is a leading cause of death and disability among young adults. The frequent cognitive, emotional and behavioral problems observed after TBI are major risk factors influencing the outcome of TBI patients. Mood disorders are the most frequent psychiatric complication of TBI, have a large impact on family functioning, interpersonal relationships, and return to work or school. Furthermore, a significant proportion of these disorders will progress to more chronic and treatment refractory forms. In spite of their clinical relevance, mood and anxiety disorders remain largely unrecognized and not adequately treated, contributing to greater disability and decreased participation in the aftermath of TBI. In this study, we will examine the efficacy of sertraline to prevent the onset of mood and anxiety disorders during the first six months after TBI. A group of 104 patients with closed TBI will be recruited immediately after resolution of posttraumatic amnesia and randomly assigned to receive six months of double-blind treatment with sertraline or placebo. Primary outcome measures will include time to onset of DSM-IV defined mood and anxiety disorders requiring immediate treatment intervention, and psychosocial outcome as measured by Community Integration Questionnaire (CIQ) scores. In addition, we will examine the effect of sertraline on frequent post-TBI behavioral disorders such as aggression, impulsivity, poor decision making and apathetic symptoms. MRI based volumetry and diffusion tensor imaging will be used to examine the structural correlates of mood and anxiety disorders as well biological predictors of treatment response and community reintegration. Early preventive treatment with sertraline would reduce sub-threshold mood and behavioral symptoms, prevent the occurrence of structural and functional brain changes associated with the onset of mood disorders, assure patient's access and participation in rehabilitation programs and, consequently, improve psychosocial outcome.